In Project 1 we aim to therapeutically deliver trophic factors or neurotransmitter enzymes to protect against age-related dysfunctions found in aged rats or transgenic mouse models of Alzheimer's disease. The degeneration of cholinergic neurons is one of the most consistent findings in AD. We propose to use viral vectors to investigate therapeutic approaches of direct gene delivery to animal models of AD primarily focused on lentiviral vectors. Three complementary strategies will be developed to reverse the morphological and behavior deficits associated with aging in normal aged rats and a transgenic mouse model of AD. The first strategy is to restore function using ChAT to replace or supplement depleted acetylcholine in aged rats. The second strategy places the emphasis on neuroprotection using the NGF gene and product to protect ChAT neurons from age related death, and enhance the function of the remaining neurons. A progression within these two strategies from constitutive to regulatable expression will be made as we improve our lentiviral vectors. The third strategy focuses on the interplay between amyloid precursor protein (APP), and the cholinergic system. Lentiviral factors delivering either NGF or ChAT will be injected into the hippocampus of transgenic animals over expressing APP to elucidate whether the cholinergic system regulates amyloid processing, alters plaque formation, or may improve behavioral performance. Functional and anatomical effects of direct gene delivery of choline acetyltransferase (ChAT) and nerve growth factor (NGF) to the aged brain have not been evaluated. Using lentiviral vectors, we can deliver these molecules to discrete populations of cells within the central nervous system (CNS), measuring the effects of direct (ChAT), or indirect (NGF) cholinergic enhancement on cognition, neuronal and synaptic changes, and amyloid processing.